title: Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity.
abstract: Ibalizumab is a humanized monoclonal antibody that binds human CD4--a key receptor for HIV--and blocks HIV-1 infection. However, HIV-1 strains with mutations resulting in loss of an N-linked glycan from the V5 loop of the envelope glycoprotein gp120 are resistant to ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the ibalizumab light chain, perhaps causing steric hindrance that disrupts viral entry. If this void contributes to HIV-1 resistance to ibalizumab, we reasoned that 'refilling' it by engineering an N-linked glycan into the ibalizumab light chain at a position spatially proximal to gp120 V5 may restore susceptibility to ibalizumab. Indeed, one such ibalizumab variant neutralized 100% of 118 diverse HIV-1 strains tested in vitro, including 10 strains resistant to parental ibalizumab. These findings demonstrate that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially enhance its activity.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
authors.forename: Ruijiang
authors.initials: R
authors.lastname: Song
authors.forename: Deena A
authors.initials: DA
authors.lastname: Oren
authors.forename: David
authors.initials: D
authors.lastname: Franco
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D003429:Cross Reactions; D024882:Drug Resistance, Viral / Q000187:drug effects; D057809:HEK293 Cells; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008958:Models, Molecular; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D023581:HIV Fusion Inhibitors; D011134:Polysaccharides; C481504:ibalizumab